4-Amino-s-triazolo-{8 4,3-a{9 {8 1,4{9 benzodiazepine

ABSTRACT

4-Amino-s-triazolo(4,3-a) (1,4)benzodiazepines of the formula IIIa: WHEREIN R1 is hydrogen, chloro of fluoro; wherein R2 is hydrogen, or fluoro with the proviso that R2 is fluoro only if R1 is fluoro, and wherein R3 is chloro, fluoro, nitro or trifluoromethyl, are prepared by reacting an s-triazolo(4,3-a) (1,4)benzodiazepine-4-carboxylic acid ester (1) with O-(2,4dinitrophenyl)-hydroxylamine and thereafter hydrolyzing and decarboxylating the product with barium hydroxide to give the compound IIIa. The invention further comprises the amides products from these amines and the pharmacologically acceptable acid addition salts thereof. The above products are useful sedatives and tranquilizers for mammals.

United States Patent [1 1 Hester, Jr.

[ 4-AMINO-S-TRIAZOLO-Et,3-a] [1,4] BENZODIAZEPINE [75] Inventor: JacksonB. Hester, Jr., Galesburg,

Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: Jan. 21, 1974 [21] Appl. No.: 434,812

Related US. Application Data [63] Continuation-impart of Ser. No.180,876, Sept, 15,

1971, abandoned.

[52] US. Cl. 260/308 R; 260/239 BD; 260/239.3 D; 260/283 R; 260/288 R;260/289 R; 260/562 B; 424/269 OTHER PUBLICATIONS Bell et a1. 11, .1.Med. Pharm. Chem., Vol. 11, pages 457 461, (1968).

Primary Examiner-Alton D. Rollins Attorney, Agent, or Firm-Hans L.Berneis [451 Sept. 2, 1975 [5 7 ABSTRACT 4-Amino-s-triazolo[4,3-a][ 1,4]benzodiazepines of the formula 111a:

Illa

wherein R is hydrogen, chloro of fluoro; wherein R is hydrogen, orfiuoro with the proviso that R is fluoro only if R is fluoro, andwherein R is chloro, fluoro, nitro or trifluoromethyl, are prepared byreacting an s-triazolo[4,3-a][ 1,4]benzodia epine-4-carboxylic acidester 1 with O-( 2,4-dinitrophenyl hydroxylamine and thereafterhydrolyzing and decarboxylating the product with barium hydroxide togive the compound 111a.

vThe invention further comprises the amides products from these aminesand the pharmacologically acceptable acid addition salts thereof.

The above products are useful tranquilizers for mammals.

sedatives and 5 Claims, N0 Drawings 1 4-AMINO-S-TRIAZOLO-[4,3-a] [1,4IBENZODIAZEPINE CROSS REFERENCE TO RELATED APPLICATION Thisapplication is a Continuation-in-Part of application Ser. No. 180,876,filed Sept. 15, 1971 and now abandoned. 1

BACKGROUND OF THE INVENTION Field of the Invention wherein R is hydrogenor chloro, and the pharmacologically acceptable acid addition saltsthereof.

The invention also encompasses the N-acyl derivatives of the compoundsof formula lIIa and lllaa.

The process of this invention comprises treating an acid ester offormula i in a solvent with a strong base and then with0-(2,4-dinitrophenyl)hydroxylamine to obtain the amino ester (II);hydrolyzing II with a base followed by acidification to obtain the freecarboxylic acid which decarboxylates spontaneously to give a compound offormula Illa as well as lllb. With barium hydroxide followed by sulfuricacid, the principal product is Illa; with sodium hydroxide andhydrochloric acid the principal product is Illb, which also has activityas a tranquilizer.

Acylation of the amines Illa and lIlb with a hydrocar- COOR' A) COOR R3R2 R1 R R l/ CHSQ 011% 3 R3 R2 R1 Illa |||b NH3 N 1 1 lllaaboncarboyxlic acid anhydride by conventional procedures gives thecorresponding amides.

DESCRIPTION OF THE PREFERRED EMBODIMENT The acid addition salts ofcompounds of formula Illa in this invention, are the hydrochlorides,hydrobromides, hydriodides,' sulfates, phosphates,cyclohexanesulfamates, methanesulfonates and the like, prepared byreacting a compound of formula lIIa with an equivalent amount of theselected pharmacologically acceptable acid.

Sedative effects of 4-amino-8-chloro-l-methyl-6-phenyl-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine are shown by thefollowing tests in mice:

Chimney test: [Med. Exp. 4, (1961)]: The effective intraperitonealdosage for 50% of the mice (ED is 6.3 mg./kg. The test determines theability of mice to back up and out of a vertical glass cylinder within30 Seconds. At the effective dosage, 50% of the mice failed doing it.

Dish test: Mice in-Petri' dishes cm.- diameter,'=5 cm. high, \partiallyembedded in woodshavings), climb outin' a very shorttime, when nottreated. Mice remaining in the dish for more. than 3 minutes indicatestranquilization. ED -equals the doseof the test compound. at which 50%of the mice re? main in the dish. The ED, (intraperitonealadministration) in this test is 4.5 mg./kg. I

. Pedestal test: The untreated mouselleaves the pedes-; tal in less thana minute to climb. back to the floor of the standard mouse box.Tranquilized mice will stay on the pedestal for more than 1 minute. TheED (intraperitoneal administration) is 4.5

mg./kg. I

Nicotine antagonism test: Mice in a group of 6 are in; jected with thetest'compound (4amino-8-chlorol-methyl-6-phenyl-4H-s-triazolo[4,3-a][ l,4] benzodiazepine). Thirty minutes later the mice including control(untreated) mice are injected with nicotine salicylate (2 mg./kg. Thecontrol mice show over-stimulation, i.e., (1) running convulsionsfollowed by (2) tonic extensor fits followed by (3) death. Anintraperitoneal dosage of 0.36 mg./kg. of

the test compound protected 50% of the mice against (2) and 0.63 mg./kg.against (3) (ED The intermediates of formula II are also activetranquilizers and sedatives, but of lesser activity, as can be seenbelow:

ED,-,,, (in mg./kg.) Ch D P Ni 4-amino-8-chloro-methyl-6-phcnyl- 71 324.5

all 1,41benzodiazepinetcarboxylic acid ethyl ester Ch Chimney test DDish test P Pedestal test Ni Nicotine test (3) The pharmaceutical formscontemplated by this invention include pharmaceutical compositionssuited for oral, parenteral and rectal use, e.g., tablets, powderpackets, cachets, dragees, capsules, solutions, suspensions, sterileinjectable forms, suppositories, bougies, and the like. Suitablediluents or carriers such as carbohydrates (lactose, proteins, lipids,calcium phosphate, cornstarch, stearic acid, methylcellulose, and thelike may be used as carriers or for coating purposes. Water and oil,e.g., coconut oil, sesame oil, safflower oil, cottonseed oil, peanutoil, may be used for preparing solu-. tions or suspensions of theactive. drug. Sweetening, coloring and flavoring agents: may be added.

For mammals and birds, food premixes, with starch, oatmeal, driedfishmeat, fishmeal, flour and the like can be prepared.

As tranquilizers, the compounds of formula Illa and Illb can be used indosages of 02-20 mg./kg., preferably 1-10 mg./ kg., in oral orinjectable preparations as described above, to alleviate tension andanxiety in mammals, or birds, such as e.g., occurs when animals. areintravel. Particularly for larger animals the low dosage range ispreferable.

Feeds for poultry or livestock can be prepared containing from 1-100grams of Illa or salts thereof per ton of feed, to achieve faster.growth, greater food efficiency, weight gain, and higherproduction ofeggs or milk.

The starting products of this invention (formula I); I

are produced as shown in the preparations.

ln carrying outltheprocess of-thisinvention, an ester compound l istreated in'solution with a strong base. As solvent for the solutiondimethylformamide, diethylformamide, dirne'thylsulfoxide,'diethylsulfoxide, dioxa'ne, diglyme, tetrahydrofuran, and-the like, canbe used. As base as alkali metal alkoxide or hydride is used, e.g.,sodium or potassium methoxide, ethoxide, potassium or sodium hydrideorthe-liker, In the preferred embodiment of this invention the reactionwith the base is carried out at 10to 20 C. over a period of 5-30minutes; The mixture may be allowed-to stand at room temperature('2030'C.-) for" /2 to 3 hours and is then cooled to 'l'0 to 15C. beforeadding'the 0;(2-,'4= clinitrophenyl') hydroxyla'ini'ne. An excessfiof5'2 O% (molar ratios) of the reactant hydroxylamine' over the startingcompound is preferred; Thereaction mixture again is allowed to stand for/2 to 3 hours. At the termination of the reaction, compound II'isisolated and purified by standard. methods such as extraction,chromatography, crystallization and the like. Compound II is thensimultaneously hydrolyzed and decarboxylated. Treating II with one-thirdN aqueous barium hydroxide in a solvent, e.g. a lower alkanol at roomtemperature and neutralizing the mixture with dilute sulfuric acid gavecompound Illa. Treating II with an elevated concentration of a base,e.g., sodium or potassium hydroxide from IN to 5N), and neutralizingwith hydrochloric acid'gave mainly compound lllb.

The treatment of II with a base is preferably carried out at roomtemperature during /2 to 3 hours, in methanol, ethanol, or 1- or2-propanol. The treatment (neutralization) of the resulting saltsolution with a mineral acideg. hydrochloric, hydrobromic, sulfuricacid,-and the like requires only minutes. Conventional means are used toisolate the product lIIa or IIIb such as removing salts e.gfbariumsulfate by filtration or extraction, followed by chromatographyrecrystallization, and the like. F

Treatment of [11a with an acid halide e.g. acetyl chloride, in pyridineor with an acid anhydride gives the corresponding amides whichare'isolated by conventional means, evaporation of solvents, extraction,chromatography, crystallization, and thelike. I

The following Preparations and Examples are illustrative of the processand products of the present invention butare not to be construed aslimiting.

PREPARATION l 2 -Benzoy1-4 -chloroacetanilide,

Acetyl chloride (81.3 g., 1.037 mole) was added 'to a stirred solutionof 2-ami'no-5-chlorobenzophenone- (200.0 g., 0.864 mole) and pyridine(68.4 g;, 0.864 mole) in dry ether (4.1 the mixture was kept at ambienttemperature for 2 hours and treated with. 500 ml. of water. The layerswere separated and the ether layer was dried over anhydrous sodiumsulfate and concentrated. Crystallization of the residue from ethylacetate- Skellysolve B hexanes gave: 124.0 g. of 2-benzoyl-4-chloroacetanilide of melting point l14-115 C. Two more crops of2-benzoyl-4'-chloroacetanilide also were obtained: 67.8 g. of meltingpoint 1 13.51l4.5

' C. and 33.0 g. of melting point ll3l 14 C.

PREPARATION 2 6-chloro-4-pheriyl-2( 1H )-quinolone The procedure(reaction of 2-benzoyl-5'- chloroacetanilide with sodium hydroxide) ofA. E. Drukker and C. I. Judd, J., Heterocyclic Chem. 3', 359 (1966) wasused for this preparation. The yield was 77%. Two other preparationshave been described: S. C. Bell, I. S. Sulkowski, C. Gochman and S. J.Childress, J. Org. Chem. 27, 562 (1962); G. A Reynolds and C. R. Hauser,J. Amer. Chem. Soc., 72, 1852 PREPARATION 32,6-Dichloro-4-phenylquinoline The procedure of A. E. Drukker and C. I.Judd, J. Heterocyclic Chem. 3, 359 (1966) was used for this preparation.The yield was 62%.

PREPARATION 4 6-Ch1oro-2-hydrazino-4-phenylquinoline A stirred mixtureof 2,6-dich1oro-4-phenylquinoline (2.7 g., 0.01 mole) and hydrazinehydrate (6.8 g.) was refluxed under nitrogen for 1 hour and concentratedin vacuo. The residue was suspended in warm water, and the solid wascollected by filtration, dried and recrystal' lized from ethylacetate-Skelly B hexanes to give 1.81 g. (67% yield) of6-chloro-2-hydrazino-4- phenylquinoline of melting point 156.5157 C.

Anal. calcd. for C H, ClN,,:

C, 66.79; H, 4.49; CI, 13.15; N, 15.58. Found: C, 67.15; H, 4.65; CI,13.19; N, 15.32.

PREPARATION 5 7-Chloro-1methyl-5-phenyl-s-triazolo[4,3-a]quinoline Astirred mixture of 6-chloro-2-hydrazino-4- phenylquinoline (1.4 g.,0.0052 mole), triethyl orthoacetate (0.925 g., 0.0057 mole) and xylene(100 ml.) was refluxed under nitrogen, for 2 hours, 40 minutes. Duringthis period the ethanol formed in the reaction was removed bydistillation through a short, glass helixpacked column. The mixture wasconcentrated to dryness in vacuo and the residue was crystallized frommethanol-ethyl acetate to give: 1.02 g. of 7-chloro-1-methyl-5-phenyl-s-triazolo ['4,3-a]-quinoline of melting point 253.5225C. and 0.26 g. of melting point 253.5-255 C. (83.9% yield). Theanalytical sample was crystallized from methylene chloride; methanol andhad a melting point 252.5253.5 C.

Anal. calcd. for C H clN t C, 69.50; H, 4.12; CI, 12.07; N, 14.31. C,69.39; H, 4.02; CI, 12.10; N, 14.49.

PREPARATION 6 5-Ch1oro-2-(3 methyl-4H-1,2,4-triazol-4- yl)benzophenone'(Oxidation of 7-chloro-1-methyl-S-phenyl-s-triazolo[4,3-

a]quino1ine) A stirred suspension of7-chloro-l-methyl-S-phenyls-triazolo [4,3-a]quinoline (2.94 g., 0.01mole) in acetone (110 ml.) was cooled in an ice-bath and treated slowlywith a solution prepared by adding sodium periodate (2 g.) to a stirredsuspension of ruthenium dioxide (200 mg.) in water (35 ml.). The mixturebecame dark. Additional sodium periodate (8 g.) was added during thenext 15 minutes. The ice bath was removed and the mixture was stirredfor 45 minutes. Additional sodium periodate (4 g.) was added and themixtures was stirred at ambient temperature for 18 hours and filtered.The solid was washed with acetone and the combined filtrate wasconcentrated in vacuo. The residue was suspended in water and extractedwith methylene chloride. The extract was dried over anhydrous potassiumcarbonate and concentrated. The residue was chromatographed on silicagel (100 with 10% of methanol ethyl acetate; 50-m1. fractions werecollected.'The product was eluted in fractions 1020 and was crystallizedfrom ethyl acetate to give: 0.405 g. of melting point 168l69.5 C. and0.291 g. of melting point 167.5-169 (23.4% yield) 0f 5-chloro-2-(3-methyl-41+ l ,2,4-triazol-4-yl )benzophenone. The analytical sample hada melting point of 168 C.

Anal. calcd. for c,,,H,.,C|N ,0;

C, 64.54; H, 4.06; Cl,-l 1.91; N, 14.11. Found: C, 64.56; H, 4.35; CI,11.97; 11.93; N, 14.29.

PREPARATION 7 Oxidation of7-ch1oro-1-methyl-5-phenyls-triazolo[4,3-a]quinoline A stirredsuspension of 7-ch1oro-1-methyl-5-phenyls-triazolo[4,3-a]quinoline (2.94g., 0.01 mole) and acetone (200 ml.) was cooled in an ice bath andtreated, dropwise, during 15 minutes with a solution prepared fromruthenium dioxide (200 mg.), sodium periodate (4 g.) and water (35 ml.).A slight exothermic reaction was noted and the mixture became dark.After 10 minutes, 29 ml. of a solution of sodium periodate (12 g.) inwater (70 ml.) was added during 10 minutes. This mixture was stirred for2 hours and then the remaining sodium periodate solution (41 ml.) wasadded during the next 3 hours. The mixture was concentrated in vacuo toremove acetone. The resulting aqueous mixture was extracted withmethylene chloride. The extract was washed with water, dried overanhydrous magnesium sulfate, and concentrated. The residue waschromatographed on silica gel (150 g.) with 2% methanol-98% chloroform;60 ml. fractions were collected. Recovered starting material was elutedin frac tions 1 1-14 and crystallized from methanol-methylene chlorideto give 0.069 g. of meltingpoint 251.5.253.5 C. A mixture of the twoproducts was eluted in fractions 15-39. Crystallization of this mixturefrom ethyl acetate gave 618 mg. (20.8%) of 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone of melting point 165.5168.Crystallization of the mother liquor from methanol gave 0.126 g.,melting point 108112 and 0.588 g. of melting point 101.5-105.5(decomposition) (19.9% yield) of a methanol solvate of 4-(2-benzoyl-4-chlorophenyl )-5-methy1-4H- 1 ,2,4-triazole- 3-carboxaldehyde.The analytical sample had a melting point l0l.5 C.

Anal. Calcd. for C -H ClN- O C, 62.68; H, 3.71; CI, 10.89; N, 12.90.Found: C, 59.37; H, 4.89; CI, 9.75; N, 11.30.

MeOH, 9.34%; H O, 0.40%. Corrected for MeOH and H C, 61.90; H, 4.06; C1,10.80; N, 12.52.

Heating the solvate in a desiccator at 70 C. at 15 mm. Hg for 72 hoursgave pure 4-(2-benzoyl-4- chlorophenyl )--methyl-4H- l ,2,4-triazole-3-carboxaldehyde.

PREPARATION 8 Oxidation of 7-chlorol -methyl5-phenyl-s-triazolo[4,3-a]quinoline A vigorous stream of ozone in oxygen was bubbled for 12hours, into a stirred, ice-cold solution of 7- chloro- 1 -methyl-5phenyl-s-triazolo[ 4,3-a]qu inoline (31.1 g., 0.106 mole) in methanol(750 ml.) and methylene chloride (500 ml.). The resulting mixture wasfiltered and the filtrate was added to an ice cold solution of sodiumiodide (47.5 g.) and acetic acid (63 ml.) in water (200 ml.). Thesolution was decolorized by the addition of sodium thiosulfate andconcentrated in vacuo. The residue was mixed with water and extractedwith methylene chloride. The extract was washed (H O), dried overanhydrous magnesium sulfate and concentrated. The residue waschromatographed on silica gel (1.5 kg.); 175 ml. fractions werecollected. Fractions ll28 were eluted with 1% methanol -99% chloroformand fractions 129-168 with 5% methanol- 95% chloroform. The firstcompound was eluted in fractions 49-60 and crystallized frommethanol-ethyl acetate to give: 0.769 g. of melting point 229.5-231(decomposition) and 0.535 g. of melting point 228 (decomposition) of7-chloro-l-methyl-S-phenyl-striazolo[4,3-a]quinolin-4(5H)-one. Theanalytical sample has a melting point 232233 C.

Anal. calcd. for C,,H, ClN,,O'.

C, 65.92; H, 3.91; Cl, 11.44; N, 13.57. Found: C. 65.46; H, 3.72; C1,11.48; N, 13.59.

Recovered starting material was eluted in fractions 66-78 andcrystallized from methylene chloridemethanol to give 0.737 g. of meltingpoint 251253.5 C. A mixture of the two remaining products was eluted infractions 73-168. Crystallization of this mixture from ethyl acetategave: 10.8 g. of melting point l66.5167.5 C., 0.987 g. of melting point166-167 C. and 2.52 g. of melting point l64-165.5 C. (45.3% yield) of5-chloro-2-(3-methyl-4H- l ,2,4-triazol-4- yl) benzophenone.Crystallization of the mother liquor from methanol gave 5.62 g. ofmelting point l40141.5C., 1.23 g. ofmelting point l0O.5-102.5(decomposition) and 1.04 g. of melting point 105- 137.5 (20.8% yield) of4-(2-benzoyl-4-chlorophenyl)- 5-methyl-4H- 1,2,4-triazole-3-carboxaldehyde.

PREPARATION 9 5-Chloro-2- 3-(hydroxymethyl 5-methyl-4H- 1,2,4-triazol-4-yl benzophenone.

A stirred mixture of 5-chloro-2-(3-methyl-4H-1,2,4-triazolo-4-yl]nenzophenone, (2.98 g., 0.01 mole) paraformaldehyde (3 g.)and xylene (100 ml.) was warmed under nitrogen, in a bath maintained at125 C. for 7 hours. The mixture was then concentrated in vacuo. Theresidue was chromatographed on silica gel 150 g.) with 3% methanol-97%chloroform. Fifty ml. fractions were collected. The product was elutedin fractions 20-44. The fractions were concentrated and the residue wascrystallized from ethanol-ethyl acetate to give: 1.64 g. of meltingpoint 138-l42 C; 0.316 g. of melt ing point 138.5141 C.;'0.43l g. ofmelting point l39l4l C. (72.8% yield) of 5-chloro-2[3-(hydroxymethyl)-5-methyl-4H-l ,2,4-triazol-4- yl]benzophenone. Theanalytical sample had a melting point of l38139 C.

Anal. calcd. for C H C1N O C, 62.30; H, 4.30; CI, 10.81; N, 12.82.Found: C, 62.23; H, 4.22; CI, 10.82; N, 11.73.

PREPARATION 10 5-Chloro-2- 3-(bromomethyl )-5-methyl-4H-l ,2,4-triazol-4-yl benzophenone A solution of 5-ch1oro-2-[3-(hydroxymethyl)-5-methyl-4H-1 ,2,4-triazol-4-yl ]benzophenone (328 mg., 0.001 mole) indry, hydrocarbon-stabilized chloroform (5 ml.) was cooled in an ice bathand treated with phosphorus tribromide (0.1 ml. The colorless solutionwas kept in the.ice bath for 55 minutes, at ambient temperature (2224C.), for 5 hours. The resulting yellow solution was poured into amixture of ice and dilute sodium bicarbonate. This mixture was extractedwith chloroform. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated. The residue was crystallized frommethylene chlorideethyl acetate to give: 0.285 g. of melting point200-240 (decomposition) and 0.030 g. of melting point 200-240 C.(decomposition) of 5-chloro-2-[3- (bromomethyl)-5-methyl-4H-1,2,4-triazol-4- yl}benzophenone. The analytical sample had a meltingpoint of 200240 C.

Anal. calcd. for C H BICIN O:

C, 52.26; H, 3.35; Br, 2046; Cl, 9.08; N, 10.76. Found: C, 52.13; 52.45;H, 3.77, 3.66; Br, 20.44;

Cl, 9.20; N, 10.43.

PREPARATION l l A solution of 5-chloro-2-[3(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone (328 mg., 0.001 mole) inthionyl chloride (2 ml.) was warmed during 40 minutes to a bathtemperature of 78 C. and kept at 7883 C. for 1 hour 25 minutes. It wasthen cooled and poured into ice water. This mixture was neutralized withsodium bicarbonate and extracted with chloroform. The extract waswashedwith brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The residue was crystallized from ethyl acetateSkellysolve B hexanes to give: 0.240 g. of melting point 144.5l47 C. and0.045 g. of melting point 144.5146.5 C. of5-chloro-2-[3-(chloromethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone. The analytical sample had amelting point of 139140C.

. PREPARATION 12 Chloro-2-[3-( iodomethyl )-5-methyl-4l-I- 1,2,4-triazol- 4-yl]benzophenone5-Ch1oro-2-[3-(chloromethylf5-methyl-4H-1 ,2,4-triazol-4-yl1benzophonone (346 mg. 0.001 mole) was added to a stirredsolution of sodium iodide (300 mg., 0.002 mole) in acetone, and theresulting mixture was stirred at ambient temperature for 6 hours 54minutes and poured into ice water. This mixture was extracted withchloroform. The extract was wahed with brine, dried and concentrated.The residue was crystallized from methylene chloride-ethyl acetate togive: 0.227 g. of melting point 185.59-192" C. (decomposition) of 5-chloro-2-[3-(iodomethyl)-5-methyl-4H-1,2,4-triazol-4- yl]benzophenone.The analytical sample had a melting point of 185200 C. (decomposition).

Anal. calcd. for C,,H,,,C||N..0;

C. 46.65; H, 299; Cl. 8.10; l. 29.00; N. 9.60. Found: C. 46.78; H, 2.88;Cl, 8.59; 1. 16.98; N. 9.23.

PREPARATION l 3 8-Chloro- 1 -methyl-6-phenyl-4H-s-triazolo[4,3-

a][ 1 ,4 ]benzodiazepine A stirred suspension of 5-chloro-2-[ 3-bromomethyl)-5-methyl-4I-I- l ,2,4-triazol-4- yl]benzophenone (391 mg,0.001 mole) in tetrahydrofuran (15 ml.) was cooled in an ice bath andtreated with a saturated solution of ammonia in methanol 12.5 ml. Theresulting solution was allowed to warm to ambient temperature and standfor 24 hours. It was then concentrated in vacuo. The residue wassuspended in water, treated with a little sodium bicarbonate andextracted with methylene chloride. The extract was washed with brine,dried with anhydrous potassium carbonate and concentrated. The residuewas crystallized from methylene chloride-ethyl acetate to give 0.220 g.of crude product of melting point 227228.5 C. Recrystallization of thismaterial from ethyl acetate gave 0.142 g. of melting point 228-229.5;(0.053 g.) of melting point 228.5229.5 C. and 0.021 g. of melting point228229.5 C. of 8-chloro-l-methyl-6- phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Reaction of the 5-chloro-2-[3-(chloromethyl)-5-methyl-4H-l,2,4-triazol-4-yl]benzophenone with ammonia in methanol alsogave 8-chloro-l-methyl-6- henyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine,but the reaction was slower. It required more than 2 days to go tocompletion.

In like manner, 782 mg. (0.002 mole) of 5-chloro-2-[3-(bromomethyl-5-methyl-4H-1,2,4-triazol-4- yl]benzophenone inmethylene chloride, cooled in a Dry Ice-methanol bath, gave withanhydrous ammonia 5 15 mg. of8-chloro-1-methy1-6-phenyl-4H-striazolo[4,3-a][1,4]benzodiazepine ofmelting point 226-227 C.

Other 8-substituted- 1-methyl-6-phenyl-4I-l-striazolo[4,3-a][1,4]benzodiazepines can beproduced from the corresponding l,3-dihydro-7-substituted-5-phenyl-ZH-l,4-benzodiazepine-2-thiones as shown in the followingpreparations 14-18:

PREPARATION l4 8-Chlorol-methyl-6-( 2,6-difluorophenyl)-4H-striazolo[4,3-a][ 1,4]benzodiazepine A solution of 6.0 g. (0.0186mole) of 1,3-dihydro-7 chloro-5-( 2,6-difluorophenyl)-2H-1,4-benzodiazepine- 2-thione and 4.14 g. (0.0558 mole) of acetic acidhydrazide in 250 ml. of l-butanol was heated under reflux. During thefirst hour a stream of nitrogen was passed through the reaction mixtureto remove the hydrogen sulfide formed. The heating was continued for 18hours in a nitrogen atmosphere. The reaction mixture was concentrated,the residue poured into water, and extracted with methylene chloride.The organic layer was dried over anhydrous sodium sulfate. Removal ofthe solvent gave 6.8 g. of orange solid which was recrystallized fromethanol to give in two crops 4.5 g. of8-chloro-1-methyl-6-(2,6-difluorophenyl)- 4H-s-triazolo[4,3-a][1,4]benzm1iazepine of melting point 2 78-279.5 C.

Anal. Calcd. for C H CIF N C. 59.22; H, 3.22; CI, 10.28; F. 11.02; N.16.26 Found: C, 59.41; H. 3.31; CI, 10.32; F, 11.06; N. 16.18.

By heating the reaction mixture at lower temperature (replacingl-butanol by ethanol) or for shorter periods of time, the open-chainintermediate, 2-(2- acetylhydrazino)-7-chloro-5-( 2,6-difluorophenyl)-3H- 1,4-benzodiazepine, can be isolated. This material, recrystallizedfrom ethanol, has a melting point of 274-277 C.

Anal. Calcd. for C H CIF N O:

C, 56.28; H. 3.61; CI. 9.77; F, 10.47; N. 15.45. Found: C. 56.02; H,3.49; CI. 9.78; F. 10.62; N. 15.53.

PREPARATION l5 A solution of 1.52 g. (0.005 mole) of 7-chloro-l,3-dihydro-S-(o-fluorophenyl )-2l-l- 1 ,4-benzodiazepine-2- thione and 1.11g. (0.015 mole) of acetic acid hydrazide in 50 m1. of l-butanol wasrefluxed for 12 hours while bubbling a stream of nitrogen through thereaction mixture. The solvent was evaporated in vacuo and the residuewas treated with water and methylene chloride. The phases were separatedand the organic layer was dried over anhydrous sodium sulfate andconcentrated to an oil. The crude oil was triturated with ethylacetate-Skellysolve B hexanesand the resulting solid was filtered togive 1.32 g. of solid of melting point 202203 C. Crystallization fromethyl acetate- Skellysolve B hexanes yielded 1.13 g. (70%) of 8-chloro-1-methyl-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 203-204 C.

Anal. Calcd. for C H CIFN C. 62.49; H, 3.70; CI. 10.85; F. 5.81; N.17.15. Found: C. 62.39; H, 3.87; CI. 10.91; F. 6.03; N. 17.11.

PREPARATION 1 61-Methyl-6-phenyl-8-(trifluoromethyl)-4H-striazolo[4,3-a][ 1,4]benzodiazepine A stirred mixture of 1,3-dihydro-5-phenyl-7-(trifluoromethyl )-2H- 1 ,4-benzodiazepine-2-thione (64.9 g.; 0.204mole), acetic acid hydrazide (45.3 g.; 0.612 mole) and methanol (2500ml.) was refluxed .under nitrogen for 24 hours. During the first twohours nitrogen was bubbled through the refluxing mixture.

The mixture was concentrated in vacuo. A suspension of the residue inwater was stirred for one hour and filtered. The solid was dried at 30C. in vacuo to give 64 g. of crude2-(2-acetylhydrazino)-7-(trifluoromethyl)- -phenyl-3H-l,4-benzodiazepine.- This material was heated in batches of -20 g. at 200C. under reduced pressure (12 mm.) until thesolid had melted andbubbling had become slow. The 'oily product was combined and stored at 4C. The crystalline material which resulted was collected by filtration,washed with ether and dried to give 33.4 g. of crude product. The'motherliquor was chromatographed on silica gel (3 kg.) with 5% methanol-95%benzene (by volume) to give additional product. The combined product wasrecrystallized from wet methylene chloride-ether in two crops: 25.2 g.,melting point l20.5l27 C. of l-methyl-6- phenyl-8 trifluoromethyl)-4H-s-triazolo[ 4, 3- a][l,4]benzodiazepine hydrate. The first crop hadultraviolet spectrum (ethanol) having A max. 219 (e 13,100 and 280 m e:3,850).

Anal. Culcd. for C,,.H,;,F;,N,:

C, 63.15; H. 3.83; F, 16.65; N. 16.37. Found for hydrate: I V

C, 59.07; H. 4.88; F, 15.90; N, 15.49;

Corrected for H O:

C, 62.73; H, 4.49; F. 16.90; N, 16.45.

Heating this product to 80 C. for a period of 72 hours at a pressure of12 mm. Hg gave water-free l-methyl-6-phenyl-8-(trifluoromethyl)-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine.

PREPARATION 17 l-Methyl-8-nitro-6-phenyl-4H-s-triazolo[4,3- a][ 1,4]benzodiazepine A stirred mixture of l,3-dihydro-7-nitro-5phenyl-2H-l,4-benzodiazepine-Z-thione (2.97 g.; 0.01 mole), acetic acidhydrazide (2.21 g.; 0.03 mole) and 1- butanol.(100 ml.) was refluxed for1.5 hours with a slow stream of nitrogen bubbling through the reactionmixture. The resulting mixture was concentrated in vacuo. The residuewas suspended in water and ex- ,tracted with methylene chloride. Theextract-was dried crystallizing this material from methanol-ethylacetate had a melting point of 23 l .5232.5 C. The ultraviolet spectrum(ethanol) had end absorption A max. 226 (e 21,500) and 259 mp.(e=18,850). Y

Anal. Calcd. for c,,N,.,N .,o c, ,63.-94;H,-4.-10; N, 21.93. Found: C.64.05; H. 3.85; N, 21.76.

PREPARATION 1s 8-Chloro-1-methyl-6-(o-chlorophenyl)-4I-Istriazolo[4,3-a][ l ,4]benzodiazepine A mixture of 1.0 g. (0.0031 mole)of 7-chlorol,3-

dihydro-5-(o-chlorophenyl )-'2H- 1 ,4-benzodiazepine-2: thione, 0.8 g.(0.0108 mole) of acetic acid hydrazide and 40 ml. of l-butanol washeated at reflux temperature under nitrogen for 24 hours. During thefirst 5 hours the nitrogen was slowly bubbled through the solution.After cooling and removing the solvent in vacuo, the product was wellmixed with water andcollected on a filter, giving 0.9g. of orange solidof melting point 2 l02l2 C. This was heated under nitrogen in an oilbath at 250 C. and then cooled. The solid was crystallized from ethylacetate, giving 0.5 g. of tan solid melting point 215 216 C. (dec.).This tan solid was dissolved in 25 ml. of 2-propanol, filtered,concentrated to 10 ml. and cooled, yielding 0.46 g; (43%) of tan,crystalline 8-chloro-1-methyl-6-(o-chlorophenyl)-4I-I-s-triazolo-[4.,3-a] [l ,4lben'zodiazepine of melting point 223225C.

A'nal. Calcd. for C,,l-I, Cl N C, 59.49; H, 3.52; C1, 2066; N, 16.32Found: C. 59.55; H, 3.78; Cl, 20.72; N, 16.24.

In the manner given in the preceding Preparations, other benzodiazepinescan be produced. Representative products, thus obtained, include:

8-nitro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-

a][l,4]benzodiazepine; 1

8-trifluorom'ethyl-1-methyl-6-(o-chlorophenyl)-4I-I-striazolo[4,3-a][ l,4]benzodiazepine;

8-nitro- 1-methyl-'6-(o-fluorophenyl)-.4H-S- triazolo[4,3-a] 1,4]benzodiazepine;

8-(trif1uoromethyl)-1-methy1 6-(o-fluoropheny1)-4H-striazolo[4,3-a] l,4]benzodiazepine;

8-trifluoromethyl-1-methyl-6-(2,6-difluorophenyl)- 4H-s-triazolo[4,3-a][l ,4]benzodiazepine; and the like.

" I PREPARATION 19 V 8-Chloro- 1 -methyl-6-phenyl-4H-s triazolo[ 4,3-=a][1,4]benzodiazepine-4-carboxylic acid ethyl ester A stirred mixtureof 8-chloro-1-methy1-6-phenyl-4I-I- s-triazolo[4',3'-a][1,4]benzodiazepine (61.8 g., 0.20 mo 1e) and'diethyl carbonate (1 liter)was treated successively with sodium-hydride (8.43 g. of a 57%suspension in "mineral oil) and ethanol (2 ml.). It was then refluxedunder nitrogen for 1.5 hours, cooled and conceritrated in vacuo. Theresidue was treated with 1 liter of ice water which contained 0.2 moleof hydrochloric acid and extracted with methylene chloride. The extractwas dried over anhydrous potassium carbonate and concentrated. Theresidual solid was boiled with ethyl acetate and collected byfiltration. It was recrystallized from methylene chloride-ethanol togive 35.7 g. of 'S-chloro-l-rnethyl-6-phenyl 4I-l-s-triazolo[4,3- a][ l,4]benzodiazepine-4- carboxylic acid ester of melting point 224225 C.(decomposition). The analytical sample had a melting point of 223224 C.(decomposition)! PREPARATION 20 8-Chlorol -methyl-6-.(2,6-difluorophenyl )-4H-striazo1o[4 ,3-a][ 1,4]benzodiazepine-4-carboxylic acid ethyl ester In themanner given inPreparation 19, a mixture .of

8-chlorol -methy]-6-( 2,6-difluorophenyl )-4H-striazolo[4,3-a][1,4]benzodiazepine, sodium hydride and diethylcarbonate was heated toreflux to give 8- chlorol -methyl-6-( 2,6-difluorophenyl )4l-I-striazolo[4,3-a][ l ,4]benzodiazepine-4-carboxylic acid ethyl ester.

PREPARATION 2 l 8Chlorol -methyl-6-( o-chlorophenyl)-4H-striazolo[4,3-a][ l,4]benzodiazepine-4-carboxylic acid methylester.

In the manner given in Preparation 19, a mixture of 8-chlorol-methyl-6-( o-chlorophenyl)-4H-striazolo[4,3-a][ 1,4]benzodiazepine,sodium hydride and dimethylcarbonate was heated to reflux to give 8-chlorol -methyl-6-( o-chlorophenyl )-4II-striazolo[4,3-a][ l,4]benzodiazepine-4 carboxylic acid methyl ester.

PREPARATION 22 8-nitro-1-Methyl-6-phenyl-4II-s-triazolo[4,3- a][ l.4]benzodiazepineA-carboxylic acid propyl ester In the manner given inPreparation l9, a mixture of l-methyl-7-nitro-6-phenyl4H-s-triazolo[4,3-a][l,4]benzodiazepine, sodium hydride and dipropylcarbonate was heatedto reflux to give l-methyl-7- nitro-6-phenyl-4H-s-triazolo[4,3-a][l,4]benzodiazepine-4-carboxylic acid propyl ester.

PREPARATION 23 8-chlorol -methyl-6-( o-fluorophenyl)-4H-striazolo[4,3-a][ l,4]benzodiazepine-4-carboxylic acid ethyl ester.

In the manner given in Preparation 19, a mixture of 8-chlorol-methyl-6-( o-fluorophenyl )-4I-I-striazolo[4,3-a][ l ,4]benzodiazepinesodium hydride and diethylcarbonate was heated to reflux to give 8-chlorol -methyl-6-(o-fluorophenyl )-4I-I-s-triazolo[4,3- a] l,4]benzodiazepine.

PREPARATION 24 S-trifluoromethyl- 1-methyl-6-phenyl-4I-I-striazolo[4,3-a][ l,4]benzodiazepine-4-carboxylicacid ethyl ester.

In the manner given in Preparation 19, a mixture of S-trifluoromethyll-methyl-6-phenyl-4I-I-striaz'olo[4,3-a][ l ,4]benzodiazepine sodiumhydride and diethylcarbonate was heated to reflux to give 8-trifluoromethyl-l -methyl-6-phenyl-4I-I-s-triazolo[4,3- a][1,4]benzodiazepine.

In the manner given in the preceding Preparations other 4-carboxylicacid esters of formula I are prepared such as:

8-chlor0-6-phenyl-4H-s-triazolo[4,3-

a][l,4]benzodiazepine-4-carboxylic acid methyl ester;

8-nitro-l -methyl-6-( o-fluorophenyl )-4H-striazolo[4,3-a][ 1.4]benzodiazepine-4-carboxylic acid ethyl ester;

8-fluorol -methyl-6-( o-chlorophenyl )-4I-I-s-triazolo- [4,3-a][ I,4]benzodiazepine-4carboxylic acid ethyl ester;

8-(trifluoromethyl)-6(o-fluorophenyl)-4I-I-striazolo[4,3-a][l,4]benzodiazepine-4-carboxylic acid isopropyl ester;

8-trifluoromethyll methyl-6 ochlorophenyl )-4H-striazolo[4,3-a][ l,4]benzodiazepine-4-carboxylic acid methyl ester;

8-nitrol -methyl-6-( o-chlorophenyl)-4Hs triazolo[4,3-a][ l,4]benzodiazepine-4-carboxylic acid methyl ester;

8-nitrol -methyl'-6-( 2,6-difluorophenyl )-4I-Istriazolo[4,3-a] I,4]benzodiazepine-4-carboxylic acid ethyl ester; and the like.

EXAMPLE I 4-Amino-8-chloro-l-methyl-6-phenyl-4H-stria1olo[4,3-a][l,4]benzodiazepineA-carboxylic acid ethyl ester.

An ice cold, stirred mixture of 8-chloro-1-methyl-6-phenyl-4I-I-s-triazolo[4,3-a][ 1,4]benzodiazepine-4- carboxylic acidethyl ester (7.62 g., 0.02 mole) in dry dimethylformamide ml.), undernitrogen, was treated with sodium hydride (0.92 g., 0.022 mole of a 57%suspension in mineral oil), and kept in the ice bath for 15 minutes andthen at ambient temperature (about 22 to 25 C.) for 2 hours. It was thencooled in an ice bath, treated with 0-(2,4-dinitrophenyl)hydroxylamine(4.38 g., 0.022 mole) [T. Sheradsky, J. Hetero'cyclic Chem. 4, 413(1967)], kept at ambient temperature for 2 hours and concentrated invacuo. The residue was suspended in ice water, neutralized with aceticacid and extracted with methylene chloride. The' extract was dried overanhydrous sodium carbonate and concentrated. The residue wascrystallized from ethyl acetate- Skellysolve B hexanes to give 5.56 g.of 4-amino-8- chlorol -methyl-6-phenyl- 4H-striazolo[4,3- a][ l,4]benzodiazepine-4-carboxylic acid ethyl ester of melting point l92-l94C. and 0.53 g. of melting point 19ll93 C. (77% yield). The analyticalsample had a melting point of l77.5l78 C.

Anal. calcd. for C- ,H, ClN O C, 60.68; H 4.58; CI, 8.96; N, 17.69.Found: C. 60.81; H. 4.52; CI. 8.95; N, 17.91.

EXAMPLE 2 4-Amino-8-chlorol -methyl-6-( 2,6-difluorophenyl4H-s-triazolo[4,3-a][ l ,4]benzodiazepine-4-carboxylic acid ethyl ester.

In the manner given in Example I, 8-chloro-lmethyl-6-(2,6-difluorophenyl )-4l-I-s-triazolo 4,3-a][l,4]benzodiazepine-4-carboxylic acid ethyl ester was treated withpotassium methoxide and then with 0-(2,4-dinitrophenyllhydroxylamine togive 4-amino-8- chlorol -methyl-6( 2,6-difluorophenyl)-4I-I-striazolo[4,3-a][ l,4]benzodiazepine-4-carboxylic acid ethylester.

EXAMPLE 3 4-Amino-8-chloro-1-methy1-6'(o-chlorophenyl)-4I-I-striazolo[4,3-a][ l,4]benzodiazepine-4-carboxy1ic acid methyl ester.

In the manner given in Example I,8-chIoro-lmethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][l,4]benzodiazepine-4-carboxylic acid methyl ester was treated withsodium hydride and then with 0-(2,4- dinitrophenyl)hydroxylamine to give4-amino-8- chlorol -methyl-6-( o-chlorophenyl )-4H-striazolo[4,3-a][ l,4]benzodiazepine-4-carboxylic acid methyl ester.

EXAMPLE 4 4-Amin0-8-nitrol -methyl-6-phenyl-4H-s-triazolo[4,3- a][l,4]benzodiazepine-4-carboxylic acid propyl ester.

In the manner given in Example 1, l-methyl-S-nitro-6-phenyl-4H-s-triazolo[4,3-a][ l ,4]benzodiazepine-4- carboxylic'acidpropyl ester was treated with potassium ethoxide and then withO-(2,4-dinitrophenyl)hydroxylamine to give4-amino-8-nitro-l-methyl-6-phenyl- 4H-s-triazolo[4,3-a][ l,4]benzodiazepine-4-carboxylic acid propyl ester. Y

EXAMPLE 5 4-Amino-8-nitrol -methyl-6-( o-chlorophenyl)-4H-striazolo[4,3-a][ l ,4]benzodiazepine-4-carboxylic acid methylester.

In the manner given in Example 1, 8-nitro-l-methyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3- a][1,4]benzodiazepine-4-carboxylicacid methyl ester was treated with potassium propoxide and then with O-(2,4-dinitrophenyl)hydroxylamine to give 4-amino-8- nitrol-methyl-6-(o-chlorophenyl )-4H-s-triazolo[4,3- a][ l,4]benzodiazepine-4-carboxylic acid methyl ester.

EXAMPLE 6 4-Aminol -methyl8-fluoro-6-(o-chloropheny1)-4H-striazolo[4,3-a][ l.4]benzodiazepine-4-carboxylicacid ethyl ester.

In the manner given in Example 1, l-methyl-8-fluoro-6-(o-chlorophenyl)-4I-I-s-triazolo[4,3- a][l,4]benzodiazepine-4-carboxylic acid ethyl ester was treated with sodiumhydride and then with 0-(2,4- dinitrophenyl)hydroxylamine to give4-amino-lmethyl-8-fluoro-6-(o-chlorophenyl)-4H-s-triazolo[4,3- a][l,4]benzodiazepine-4-carboxylic acid ethyl ester.

EXAMPLE 7 4-Amino-8-trifluoromethyll-methyl-6-phenyl-4H-striazolo[4,3-a][ l ,4]benzodiazepine-4-carboxylicacid ethyl ester.

In the manner given in Example 1, 8-trifluoromethyl-1-methyl-6-phenyl-4I-I-striazolo[4,3- a][l,4]benzodiazepine-4-carboxylic acid ethyl ester was treated with sodiumisopropoxide and then with O- (2,4-dinitrophenyl)hydroxylamine to give4-amino-lmethyl-8-triflu0romethyl-6-phenyl-4I-I-s-triazolo[4,3- a][l,4]benzodiazepine-4-carboxylic acid ethyl ester.

EXAMPLE 84-Amino-8-trifluoromethyl-1-methyl-6-(ochlorophenyl)-4H-s-triazolo[4,3-a][ l,4]benzodiazepine-4-carboxylic acid methyl ester.

EXAMPLE 9 4-Amino-8-chlorol -methyl6-phenyl-4H-striazolo[4,3-a][1,4]benzodiazepine.

A stirred solution of 4-amino-8-chloro-l-methyl-6-phenyl-4H-s-triaz0lo[4.3-2H l .4Ibenzocliazepinel carboxylic acid ethylester (3.96 g., 0.01 mole) in ethanol ml.) was treated with 33.6 ml. ofO.327l\l barium hydroxide and kept at arnoier. temperature I hour. Itwas then concentrated in vacuo and the residue was dissolved in waterand neutralized with 10 ml. of 1.037N sulfuric acid. The solid bariumsulfate thus ob tained, was collected by filtration and washed withwater. The combined filtrate was concentrated in vacuo. The residue wasdissolved in absolute ethanol and the solution was concentrated invacuo. The resulting material was crystallized from methanol-ethylacetate to give 2.04 g. of 4-amino-8-chloro-l-methyl-6-phenyl-4I-I-s-triazolo[4,3-a][ 1,4]benzodiazepine of melting point 208 C. dec.

Anal. calcd. for C, H ,ClN,-,:

C, 63 06; H, 4.36; Cl, 10.95; N. 21.63. Found: C, 62.87; H, 4.34; Cl,l0.88; N, 21.64.

EXAMPLE l0 4-Amino-8-chlorol -methyl-6-( 2,6-difluorophenyl4H-s-triazolo[4,3-a][ l ,4]benzodiazepine.

In the manner given in Example'9, 4-amino-8-chlorol-methyl-6-(2,6-difluorophenyl )-4I-l-s-triazolo 4,3- a] [-l,4]benzodiazepine-4carboxylic acid ethyl ester was treated with bariumhydroxide and then the mixture was neutralized with sulfuric acid togive 4-amino- 8-chlorol -methyl-6-( 2,6-difluorophenyl )-4I-I-striazolo[4,3-a][ l ,4]benzodiazepine.

EXAMPLE 1 l 4-Amino-8-chlorol -methyl-6-(o-chlorophenyl)-4H-striazolo[4,3-a][ 1,4 ]benzodiazepine.

In the manner given in Example 9, 4-amino-8-chlorol-methyl-6-(o-chlorophenyl )-4H-s-triazolo 4,3- a][l,4]benzodiazepine-4-earboxylicacid methyl ester was treated with barium hydroxide and then the mixtureneutralized with sulfuric acid to give 4-amino-8- chlorolmethyl-6-(o-chlorophenyl)-4I-I-striazolo[4,3-a][ l ,4]benzodiazepineEXAMPLE 1 2 4-Amino-8-nitrol -methyl-6-phenyl-4H-s-triazolo[4,3- a][l,4]benzodiazepine.

In the manner given in Example 9, 4-amino-8-nitro-1-methyl-6-phenyl-4I-I-s-triazolo[4,3-a][l,4]benzodiazepine-4-carboxylic acid propyl ester was treated withbarium hydroxide and then the mixture was neutralized with sulfuric acidto give 4-amino- S-nitrol -methyl-6-phenyl-4H-s-triazolo 4-,3

a] l ,4]benzodiazepine.

EXAMPLE l3 4-Amino-8-nitrol -methyl-6-( o-chlorophenyl)-4H-striazolo[4,3-a][ 1,4]benzodiazepine.

In the manner given in Example 9, 4-amino-8-nitrol-methyl-6-(o-chlorophenyl )-4H-s-triazolo- 4,3-

a][l,4]benzodiazepine-4-carboxylic acid methyl ester was treated withbarium hydroxide and then the mixture was neutralized with sulfuric acidto give 4-amino- 8-nitro-1-methyl-6-(o-chlorophenyl)-4I-I-s-triazolo-[4,3-a][1,4]benzodiazepine.

EXAMPLE l4 4-Amino-8-fluoro- I -methyl-6-(o-chlorophenyl)-4l-l-striazolo[4,3-a][ 1,4]benzodiazepine.

In the manner given in Example 9,4-amino-8-fluorol-methyl-6-(o-chlorophenyl )-4H-s-triazolo[4,3- a][ l,4]benzodiazepine-4-carboxylic acid ethyl ester was treated with bariumhydroxide and then .the mixture was neutralized with sulfuric acid togive 4-amino- 8-fluorol -methyl-6-( o-chlorophenyl)-4I-I-striazolo[4,3-a][ l ,4]benzodiazepine.

EXAMPLE 1 54-Amino-8-trifluoromethyl-1-methyl-6-phenyl-4H-striazolo[4,3-a] 1,4]benzodiazepine.

EXAMPLE 1 6 4-Amino-8-nitro-1-methyl-8-nitro-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

In themanner given in Example 9,4-amino-8-nitrol-methyl-6-(o-chlorophenyl )-4H-s-triazolo[4,3-a][1,4]benzodiazepine-4-carboxylic acid methyl ester was treated withbarium hydroxide and then the mixture was neutralized with sulfuric acidto give 4-amino- S-nitrol -methyl-6-( o-chlorophenyl)-4I-I-striazolo[4,3-a][1,4]benzodiazepine.

EXAMPLE l7 4-Amino-S-trifluoromethyll-methyl-6-(ochlorophenyl)-4I-I-s-triazolo[4,3- a] 1,4]benzodiazepine.

In the manner given in Example 9, 4-amino-8- trifluoromethyl- 1-methyl-6-( o-chlorophenyl)-4I-l-striazolo[4,3-a][1,4]benzodiazepine-4-carboxylic acid methylester was treated with barium hydroxyde and then the mixture wasneutralized with sulfuric acid to give 4-amino-8-trif1uoromethyll-methyl-6-( ochlorophenyl)-4I-I-s-triazolo[4,3- a] 1 ,4]benzodiazepine.

EXAMPLE 1 8 4Amino-8-chloro- 1 -methyl-6-phenyl-6I-I-striazolo[4,3-a][1,4]benzodiazepine.

A stirred suspension of 4-amino-8-chloro-l-methyl-6-phenyl-4I-I-s-triazolo[4,3-a][ 1,4 lbenzodiazepine-4- carboxylic acidethyl ester (0.792 g., 0.002 mole) in ethanol (25 ml.) was treated with2.5 ml. of 1N sodium hydroxide and kept at ambient temperature for 1 hr.50 min. It was then concentrated in vacuo. A solution of the residue inwater was neutralized to pH 6.8 with dilute hydrochloric acid and thenconcentrated in vacuo. The residue was mixed with absolute ethanol andconcentrated. The resulting material was extracted with chloroform. Theproductwas mixed with absolute ethanol and concentrated. The resultingmaterial was extracted with chloroform. The product obtained from thechloroform extract was crystallized first from methanol-ethanol and thenfrom methanol to give 0.282 g. of 4-amino-8-chlorol-methyl-6-phenyl-6H-striazolo[4,3-a][1,4]benzodiazepine of melting point278279.5 C. dec.

Anal. calcd. for C I-I CIN C, 63.06; H, 4.36; CI, 10.95; N, 21.63.Found: C, 62.71; H, 4.44; CI, 10.95; N, 21.30.

, EXAMPLE 19 4-Amino-8-chlorol -methyl-6-( 2,6-difluorophenyl6I-I-s-triazolo[4,3-a][ l ,4]benzodiazepine.

In the manner given in Example 18, 4-amino-8-chloro-1-methyl-6-(2,6-difluorophenyl)-4I-I-s triazolo[4, 3-a][ 1,4]benzodiazepine-4-carboxylic acid ethyl ester was treated with 1.2Naqueous sodium hydroxide and then the mixture was neutralized withdilute hydrochloric acid to give4-amino-8-chloro-lmethyl-6-(2,6-difluorophenyl)-6I-I-s-triazolo[4,3-

a] l ,4]benzodiazepine.

In the manner given in the preceding examples, other4-amino-triazolobenzodiazepines can be prepared. Representativecompounds thus obtained comprise:

4-amino-8-chloro-methyl-6-( o-fluorophenyl )-4l-I -striazolo[4,3-a][ l,4]benzodiazepine;

4-amino-8-nitrol -methyl-6-(o-fluorophenyl)-4I-I-striazolo[4,3 a][1,4]benzodiazepine;

4-amino-8-nitrol -methyl-6-( 2,6-difiuorophenyl)-4H- s-triazolo[4,3-a][1,4]benzodiazepine;

4-amino-8-trifluoromethyll -methyl-6-(2,6-

difluorophenyl)-4H-s-triazolo[4,3- a] 1,4]benzodiazepine;

4-amino-8-nitro-6-( 2 ,6-difluorophenyl-4I-I-striazolo[4,3-a][1,4]benzodiazepine; and the like.

Treatment of the compounds of formula IIIA with a pharmacologicallyacceptable acid such as hydrochloric, hydrobromic, phosphoric, sulfuric,acetic, propionic, toluenesulfonic, naphthalene-B-sulfonic,methane-sulfonic, tartaric, citric, lactic, malic, maleic, orcyclohexanesulfamic (acids) produces the pharmacologically acceptablesalts of these compounds of formula IIIA. The salts can be used for thesame purposes as the free base compounds of formula IIIA.

Salt formation is achieved in conventional manner by reacting thecompounds of formula IV with an excess of a selected acid in a suitablemedium e.g. water, alkanol, ether, or acetone, and recovering the saltby evaporating the solvent, preferably in vacuo.

I claim:

1. A 4-amino-s-triazolo[4,3-a][ 1,4]benzodiazepine of formula IIIa:

Illa

wherein R is hydrogen, chloro or fluoro; wherein R is hydrogen, orfluoro, with the proviso that R is fluoro only if R is fluoro; wherein Ris chloro, fluoro, nitro, or trifluoromethyl; and the pharmacologicallyacceptable acid addition salts thereof.

2. A compound according to claim 1 of the formula IIIaa:

lllaa a] l ,4]benzodiazepine.

1. A 4-AMINO-S-TRIZOLO(4,3-A) (1.4)BENOZODIAZEPINE OF FORMULA 111A:
 2. Acompound according to claim 1 of the formula IIIaa:
 3. A compoundaccording to claim 2 wherein R1 is hydrogen, and which is therefore4-amino-8-chloro-1-methyl-6-phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepine.4. A compound according to claim 2 wherein R1 is chloro and the compoundis therefore4-amino-8-chloro-1-methyl-6-(o-chlorophenyl)-4H-s-triazolo(4,3-a)(1,4)benzodiazepine.
 5. A compound according to claim 1 wherein R1and R2 are fluoro, and R3 is chloro, and the compound is therefore4-amino-8-chloro-1-methyl-6-(2,6-difluorophenyl)-4H-s-triazolo(4,3-a)(1,4)benzodiazepine.